Subunit specificity and modulation of N-methyl-D-aspartate receptor mediated intracellular calcium responses.

Format:

Book

Thesis/Dissertation

Author/Creator:

Grant, Elfrida Ruth.

Contributor:

Lynch, David, advisor.

University of Pennsylvania.

Language:

English

Subjects (All):

Pharmacology.

Neurosciences.

Molecular biology.

0307.

0317.

0419.

Penn dissertations--Pharmacological sciences.

Pharmacological sciences--Penn dissertations.

Local Subjects:

Penn dissertations--Pharmacological sciences.

Pharmacological sciences--Penn dissertations.

0307.

0317.

0419.

Physical Description:

145 pages

Contained In:

Dissertation Abstracts International 59-07B.

System Details:

Mode of access: World Wide Web.

text file

Summary:

The NMDA receptor is an ionotropic glutamate receptor that underlies a diversity of physiological and pathophysiological processes in the brain. This receptor exhibits a variety of unique functional and pharmacological characteristics including high calcium permeability and voltage-dependent magnesium block. Two main types of NMDA receptor subunits are the NR1 family, which includes eight mRNA splice variants arising from a single gene, and the NR2 family, which includes four separate gene products termed NR2A-D. Recombinant expression of these subunits in heterologous systems recapitulates many functional and pharmacological characteristics of native NMDA receptors in a subunit-specific manner. This thesis examines the subunit specificity and modulation of recombinant NMDA receptor mediated intracellular calcium increases in a mammalian, non-neuronal expression system. The data show that combined expression of NR1 and NR2 subunits is sufficient to produce glutamate activated increases in intracellular calcium. The calcium responses are glutamate concentration dependent, sensitive to open-channel blocking agents, and dependent upon the presence of extracellular calcium. The magnitude of the calcium response is subunit specific, and depends upon the type of NR2 subunit that is included. NMDA receptor subunit combinations that exhibit lower calcium permeability and lower toxicity also display smaller intracellular calcium rises. The data also show that phorbol esters modulate recombinant NMDA receptor mediated calcium responses in a manner consistent with the activation of protein kinase C. Phorbol ester modulation varies with the type of subunits that are coexpressed. Phorbol esters potentiate calcium responses of receptors containing NR2A or NR2B subunits, but attenuate responses of receptors containing NR2C or NR2D subunits. The potentiation localizes to a discrete region in the C-terminus of NR2A, while the attenuation localizes to an alternatively spliced region of NR1. Collectively, these results indicate that heterogeneity of NMDA receptor mediated intracellular calcium responses and modulation by protein kinase C may in part stem from a diversity of receptor types comprised of variable heterologous subunits. This analysis of these NMDA receptor properties is directly relevant to an understanding of the underlying mechanisms involved in synaptic plasticity, learning and memory, neuronal development, and excitotoxic neuronal death.

Notes:

Thesis (Ph.D. in Pharmacological Sciences) -- University of Pennsylvania, 1998.

Source: Dissertation Abstracts International, Volume: 59-07, Section: B, page: 3364.

Adviser: David Lynch.

Local Notes:

School code: 0175.

ISBN:

9780591940701

Access Restriction:

Restricted for use by site license.